Abstract The past four years of NIH/NIDA support has enabled a highly successful translational research study of acute hepatitis C virus HCV infection in young injection drug users (IDU), and this application proposes to build on and expand our scientific aims. HCV remains a problematic human pathogen; it is the most common blood borne infection in the U.S. It chronically infects up to 170 million people worldwide and causes an estimated 460,000 deaths per year, primarily due to cirrhosis, liver failure and hepatocellular cancer. Young IDU comprise the population most at risk and with the highest incidence rates (10-40%). Current treatments cure only ~50% and are too toxic for many patients; new ones are likely to have the same limitations. A protective vaccine is plainly needed to prevent productive HCV transmission in at-risk groups. Better understanding of the natural history, detailed correlates of protective immunity, and host genetic factors which impact acute HCV infection (within the first 12-24 weeks after inoculation) is likely to provide the necessary guide for vaccine and therapeutic development. For the majority of persons that are infected, the acute phase lasts six months; and those that remain viremic beyond six months will remain chronically infected. Accurate analyses of the rate, time-course, and immunological predictors of viral clearance in natural HCV infection, have been limited by the relative lack of acute cases available for prospective scientific study as well as lack of generalizability to the population most at risk (IDU). In the past four years, we have characterized acute HCV infection outcomes, clearance rates, transmission dynamics in injecting partners, immunological correlates (HCV-specific CD4+ and CD8+ cellular responses) of clearance, and acute HCV treatment candidacy. This application seeks a five-year renewal to continue and expand our multidisciplinary investigation of acute HCV infection. Our prospective study of 95 acute HCV infections has confirmed and shown robust associations between gender and HCV infection, with females clearing HCV at three times the rate of their male counterparts. Gender has been vastly understudied with respect to HCV infection (and other infections). We have also shown a cycle of recurring infection followed by clearance, demonstrating immune responses may potentially protect from persistent chronic infection. We will examine the effect of gender in more depth, and assess whether gender differences in clearance and reinfection and reclearance are explained by differences in lipid profiles, genetics, immunological responses, and/or injecting behaviors. We will continue the study of transmission dynamics in HCV discordant injecting partnerships to examine transmission events and quantify infectivity, examine the effect of viral load on infectivity and to examine whether susceptibility to infection may differ by gender. We will expand our immunological studies to examine both innate and adaptive cellular immune responses to include NK/T and Tregs. Finally, we add a significant new aim, to study host genetics; assessing the impact of gender-specific polymorphisms in the HCV co-receptor SR-BI on host lipoprotein response to HCV infection. All of these studies will expand the depth and breadth of knowledge regarding acute HCV infection and clearance, including host control of HCV, overall and by gender, to inform improved vaccine designs and potentially therapeutic approaches.